Abstract Immune checkpoint inhibitors like ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) are revolutionizing cancer treatment. Understanding the genetic basis of response and resistance to immune checkpoint inhibitors are critical for improving outcomes with current agents and for developing new ones. Patients can undergo dramatic remissions after treatment while others reap no benefit. Furthermore, the immune phenotype shows substantial temperospatial variability and is influenced by multiple variables. The rationale of this project is that there is a fundamental genetic basis underlying response to immune checkpoint inhibitors that is poorly understood. Our preliminary data demonstrates that response to immune checkpoint blockade is strongly determined by the tumor mutation landscape and dictated by a specific neoantigen repertoire. We will apply a conceptually and technically innovative, systematic, multidisciplinary, and highly collaborative approach to elucidate the neoantigen landscape underlying response to immune checkpoint inhibitors. Our contribution here is expected to provide unparalleled mechanistic detail on how immune checkpoint inhibitors function and to provide biomarkers to identify patients who will benefit from PD-1 blockade. Furthermore, building on data showing that resistance may be mediated by immune pressure and immunoediting, we will shed light into how resistance to these drugs develop, providing definitive evidence for causal mechanisms of anti-tumor immunity. Should our work succeed, we envision substantial utility for similar studies for other cancers. Such an understanding will provide great insight into the mechanisms underlying how immune checkpoint blockade works, provide much needed precise biomarkers, and establish a foundation to develop more effective immunotherapy.